Method for the nitration of phenolic compounds

ABSTRACT

A method for the regioselective ortho-directed nitration of phenolic compounds useful for the preparation of ortho-nitro-phenols according to formula (I) is described.

[0001] This invention relates to a method for the nitration of phenoliccompounds, which are useful for the preparation of ortho-nitro-phenols.

[0002] The nitration of aromatic compounds via electrophilic aromaticsubstitution is a fundamental organic reaction which has been describedand reviewed extensively in the chemical literature (Olah, G. A. et al.,Nitration: Methods and Mechanisms, VCH, New York, 1989 and Taylor, R.,Electrophilic Aromatic Substitution, J. Wiley & Sons, Chichester, 1990).Somewhat surprisingly however, despite this wealth of information, mostcommercially important industrial processes still employ ‘classical’technology requiring mixtures of nitric and sulphuric acid. The use ofsuch corrosive reagents (usually in excess) creates seriousenvironmental issues and the treatment and disposal of ‘used’ acids isexpensive. Pertinent aspects from the viewpoint of chemistry areproblems associated with over-nitration and the formation of unwantedoxidised by-products, which are often difficult to remove from thewanted product. Additionally, another serious issue with the nitrationof aromatic compounds concerns the product distribution in terms of theortho:meta:para isomer ratio (i.e. regioselectivity). It is desirablefor an industrial nitration process to display a good degree ofregioselectivity in this respect where regioisomer formation is possibleand it is commonly the case that the para-nitro isomers in particularare the commercial products of interest. This regioselectivity isdetermined by steric factors and/or electronic and solvent effects. Thenitration of, for example, an aromatic ring containing say, anelectron-donating substituent (-alkyl, —OH, —O-alkyl etc.) normallygives rise to a mixture of predominantly ortho- and para-nitratedproducts, usually following a statistical distribution. Steric bulk ofthe nitrating reagent and/or of substituents on the aromatic ring tendsto favour formation of the para-product. In many cases, the use ofsupported reagents and catalysts can also be employed to influence morefavourably the formation of the para-isomer (Smith, K., Solid Supportsand Catalysts in Organic Synthesis; Ellis Horwood: Chichester, 1992).

[0003] Logically therefore, the nitration of aromatic phenolic (Ar—OH)compounds without substituents other than hydrogen at the para-positionpresents particular problems where the formation of ortho- andpara-products is possible due to the strongly activating effect of theelectron-donating hydroxy group (where para-substituents are present,e.g. alkyl, the para-position is not available to undergo electrophilicaromatic substitution and in such cases, only ortho-nitrated productsare obtained). The use of strong mixtures of acids usually gives rise todeeply-coloured and complex reaction mixtures due to oxidativedegradation of the substrate. Nitration of phenol itself can be easilyachieved under milder conditions using dilute nitric acid in chlorinatedsolvent in reasonable combined yield (61%) with a 1:2.3 ratio ofortho:para-nitrophenol isomers (Vollhardt, K. P. C. and Schore, N. E.,Organic Chemistry, 2^(nd) ed; W. H. Freeman, New York, 1994). Nitrationusing sodium nitrate in sulphuric acid gives also a 61% combined yieldwith a ratio of 1.4:1 of ortho:para isomers (Vogel, A. I., Vogel'sTextbook of Practical Organic Chemistry, 5^(th) ed; J. Wiley & Sons, NewYork, 1989). Recently, a three-step para-selective nitration of phenolderivatives was claimed (Kanno, H. et al., DE 19723214 A1) and otherpara-selective nitrating reagents have been reported including novelmetallic nitrate dinitrogen tetroxide complexes (Firouzabadi, H. et al.,Synth. Commun., 27(19), 3301-3311 (1997); Iranpoor, N. et al., Synth.Commun., 28(15), 2773-2781 (1998)), metal nitrates under non-aqueous andaprotic conditions (Firouzabadi, H. et al., Iran. J. Chem., 16(2), 48-58(1997)) and ionic complexes of dinitrogen tetroxide with 18-crown-6(Iranpoor, N. et al., Synth. Commun., 29(19), 3295-3302 (1999)).

[0004] Not surprisingly, far fewer methods have been described for theselective ortho-nitration of para-unsubstituted phenolic compounds.Lanthanide (III) nitrate salts in refluxing ethyl acetate was reportedfor the selective meta-directed nitration of 3-substituted phenols (Gu,S. et al., Synth. Commun., 27(16), 2793-2797 (1997)) but theselanthanide reagents are prohibitively expensive and the reaction itselfevolves fumes of toxic nitrogen dioxide gas.

[0005] The selective ortho-directed nitration of a few phenoliccompounds has received some aftention due to the potential usefulness ofthe products. A two-step procedure for the selective ortho-directednitration of 3-methoxyphenol involving nitrosation followed by oxidationto give 2-nitro-5-methoxyphenol has been described (Maleski, R. J.,Synth. Commun., 23(3), 343-348 (1993)) although the overall yield wasrelatively low and the regioselectivity of nitrosation was undoubtedlyenhanced in this particular case by the presence of the stronglyortho/para-directing methoxy group (due to steric reasons, thepara-position relative to the methoxy group would be favoured in thiscase). A single-step nitration methodology would of course be preferableto a multi-step approach. The so-called ‘chaperon’ effect (Strazzoloni,P. et al., Bull. Chem. Soc. Jpn., 68(4), 1155-61(1995)) described forthe selective ortho-directed nitration of alkylbenzenes could not bedirectly used for oxidation-sensitive phenolic compounds (Strazzoloni,P. et al., J. Org. Chem., 63(4), 952-958 (1998)). A near selectiveortho-nitration of phenol using a microemulsion solution in the presenceof dilute nitric acid was claimed (Chhatre, A. S. et al., J. ColloidInterface Sci., 158(1), 183-187 (1993)) but the method has obviousdisadvantages for general and larger-scale preparative purposes. Veryhigh selectivity was also observed with nitronium tetrafluoroborate anda surfactant in acetonitrile (Pervez, H. et al., Tetrahedron, 44, 4555(1988)) but these conditions and reagents are again inconvenient forlarger-scale nitrations.

[0006] Somewhat more interesting is the nitration of phenol using‘claycop’, essentially clay supported cupric nitrate which is reportedto afford a 92% yield of ortho-nitrophenol (Gigante, B. et al., J. Org.Chem., 60, 3445-3447 (1995)). Although highly ortho-selective (13:1,ortho:para) and high-yielding, the ‘claycop’ reagent is not readilyavailable from commercial sources and is also very expensive.Preparation of the reagent is tedious, the loading (mmol reagent pergram of clay support) is low and it should be stored for only shorttimes and at low temperature (˜4° C.). Additionally it is presumed thatthe actual nitrating reagent itself is in fact in situ formed acetylnitrate (CH₃CO—ONO₂), a known and potentially explosive compound notnormally isolated. These nitration reactions are rather exothermic withuncertain induction periods and when using larger quantities, sometimesviolent with strong evolution of red-brown gas. Strict safety measuresmust be applied when using such compounds, which due to their hazardousnature are not amenable to larger-scale preparations. A laterpublication described the nitration of phenol using acyl nitratesadsorbed on silica gel (Rodrigues, J. A. R. et al., Tetrahedron, 55,6733-6738 (1999)) which was claimed to improve stability of thenitrating reagent. Although almost identical selectivity and yield wasobtained as for the aforementioned ‘claycop’ procedure, it does notavoid the inconvenient, expensive and dangerous preparation of the acylnitrates and requires subsequent adsorption onto silica gel. Due to thehazardous nature of these materials it would be dangerous to attempt thereaction above the 50mmol scale as indicated by the authors. Notably,although the reagent worked extremely well for phenol itself, theortho-selectivity when applied to other phenolic compounds wasconsiderably lower (e.g. for isovanillin, 0.6:1, ortho:para) indicatingthat the method is not universally regioselective. Another example ofthe nitration of isovanillin using 70% nitric acid in cold acetone(Napoletano, M. et al., WO 99/32449, PCT/EP98/08292) was claimed to givea 74% combined yield of nitrated isomers with only slightly improvedselectivity for the ortho-nitrated product (ortho:para, 1.5:1) which wasnot thereafter isolated in pure form.

[0007] The utility of alkyl nitrates as potentially useful reagents forthe selective ortho-directed nitration of para-un/substituted phenoliccompounds has not been described in the chemical literature. Onenon-related report describes the combination of n-butyl nitrate and anunusual acid catalyst (Nafion-H) for the nitration of alkylbenzenesonly, with clear preference for formation of the less-hinderedpara-nitrated product over the ortho-nitrated isomer (Olah, G. et al.,J. Org. Chem., 43(24), 4628-4630 (1978)). Other drawbacks include therelatively low stability of the particular alkyl nitrate used and theuse of a very expensive catalyst. The use of methyl nitrate for asimilar reaction described earlier (Olah, G. et al., Synthesis, 488(1973)) would be highly undesirable due to the potentially explosivenature of methyl nitrate. A Chinese group recently claimed a similarnitration of some alkylbenzenes using a different catalyst (zeoliteHZSM-5) but again the selectivity was enhanced for the para-position(Peng, X. et al., Nanjing Ligong Daxue Xuebao, 23(6), 539-541 (1999)).

[0008] U.S. Pat. No. 3,694,513 relates to a method for nitratingalkylphenols with nitric acid in the presence of a secondary or tertiaryalcohol, a secondary alkyl nitrate, an aldehyde or a ketone.

[0009] There is lacking therefore in the prior art, a safe, economical,scaleable and generally applicable nitration methodology that may beused for the high-yielding and regioselective ortho-directed nitrationof phenolic compounds especially where the formation of mixtures ofisomeric nitro-products and/or formation of oxidised by-products ispossible.

[0010] It is an object of the invention to provide a useful,high-yielding and generally applicable method for the regioselectiveortho-directed nitration of phenolic compounds. A further object of theinvention is to provide a method which avoids the disadvantages of theprior art.

[0011] Such compounds are particularly useful as pharmaceuticallyeffective compounds, or precursors or intermediates in the manufacturethereof. For instance such compounds may be used in the manufacture ofcatechol-O-methyl transferase (COMT) inhibitors, which are used in thetreatment of central and peripheral nervous system disorders, such asParkinson's disease.

[0012] According to one aspect of the invention there is provided amethod for the preparation of compounds of formula I

[0013] wherein: the terms R′ and R″ may be the same or different andrepresent: hydrogen; lower alkyl; hydroxy; lower alkoxy; halogen; thegroup —CO—R¹, wherein R¹ signifies hydrogen, hydroxy, alkylaryl,alkylheterocycloalkyl or optionally substituted saturated or partiallyunsaturated lower alkyl or aryl group, or R¹ signifies the group —O—R²,wherein R² signifies a lower alkyl or aryl group; the group —C═N—R^(a),wherein R^(a) signifies NHR^(a), wherein R^(a) represents optionallysubstituted lower alkyl or aryl group, or OR^(b) group, where R^(b)signifies hydrogen, lower alkyl or lower alkanoyl; the group—GR^(c)R^(d), where R^(c) signifies an optionally substitutedalkylidene, where R^(d) represents OR^(e) group where R^(e) signifiesoptionally substituted lower alkanoyl or aryl group; or R′ and R″ takentogether signify an optionally substututed saturated or partiallyunsaturated carbocyclic ring; m and n are independently 0, 1 or 2; theterm lower alkyl means a carbon chain, straight or branched, containingfrom one to six carbon atoms; the term halogen means fluorine, chlorine,bromine or iodine; the term heterocycloalkyl means a five orsix-membered cyclic ring incorporating one or two atoms of oxygen,sulphur or nitrogen; the term aryl means a phenyl or naphthyl groupoptionally substituted by alkoxy, halo or nitro groups; said methodcomprising reacting a phenolic compound of formula II:

[0014] wherein the terms R′ and R″, m and n are defined above, with analkyl nitrate of formula (III)

R³—ONO₂  FORMULA III

[0015] where R³ represents an alkyl group straight or branched,containing preferably from one to sixteen carbon atoms, or R³ representsa cycloalkyl group containing either five or six carbon atoms.

[0016] The reaction is preferably carried out in the presence of an acidcatalyst in a substantially inert solvent.

[0017] Preferred alkyl nitrates include isopropyl nitrate, isoamylnitrate and isooctyl nitrate (2-ethylhexyl nitrate). Compounds offormula (III) are known and many are commercially available, or they canbe made by those skilled in the art (e.g. Olah, G. et al., Synthesis,(2), 207-208 1993)). The nitration reaction may be carried out bystirring the phenolic compound of formula II with usually an excess ofthe preferred alkyl nitrate (1.2-2.5 molar equivalents) in inertsolvents such as hydrocarbons, chlorinated alkanes, ethers or aproticdipolar solvents, or the reaction can be run in a mixture of the abovementioned solvents. The reaction is run with the use of mineral ororganic acid catalysts such as, for example, sulphuric acid(concentration 20-96%), hydrochloric acid, phosphoric acid, formic acidor trifluoroacetic acid, neat, or if preferred, adsorbed onto inertsupports such as for example, silica gel. Alternatively a Lewis acid maybe used, such as for example, boron trifluoride etherate. If desired,the reaction may be run using a phase-transfer co-catalyst such as atetraalkylammonium halide or hydrogensulphate salt (1-5 mol%). Thereaction may be performed at various temperatures and pressures e.g.between 0° C. and the boiling temperature of the reaction mixture at thepressure used. The reaction product/s may be simply isolated afterwashing the reaction mixture with water and evaporation of the reactionsolvent. If necessary, separation of the major ortho-nitrated productfrom any minor nitro-isomer contaminants or by-products present in thecrude product can be rapidly achieved by distillation or chromatographyon a suitable stationary phase such as silica gel or alumina, using anappropriate solvent system for elution. More conveniently, the crudeproduct may be recrystallised from a suitable solvent in which thewanted ortho-nitrated product has more limited solubility than anycontaminating nitro-isomers or by-products. The purified products maythen be characterised by analytical comparison with authentic standards(e.g. TLC) and/or the position of nitration can be rapidly determined byNMR spectroscopy. An advantage of this method is that it is highyielding; the overall yield of this nitration reaction frequentlyexceeding 75%. Another advantage of this method is that it isregioselective, with the regioselectivity favouring predominantformation of the ortho-nitrated product.

[0018] For avoidance of doubt, it is stated that in formula I, R′ and R″may be substituted on any position on the phenyl group.

[0019] Additionally, it is envisioned that compounds represented byformula I may be used as precursors or intermediates in the productionof further pharmaceutically active/effective compounds. According toanother aspect of the invention there is provided a method for thereparation of a compound of formula IV:

[0020] where R₄ and R₅ are the same or different and signify hydrogen,optionally substituted lower alkanoyl or aroyl, optionally substitutedlower alkoxycarbonyl, or optionally substituted lower alkylcarbamoyl; R₆signifies hydrogen or optionally substituted alkanoyl or aroyl group; R₇signifies optionally substituted saturated or partially unsaturatedlower alkyl or aryl group, or taken together with R₆ signifies anoptionally substituted saturated or partially unsaturated carbocyclicring; A signifies oxygen or NR₈ group, where R₈ signifies NHR₉ where R₉signifies optionally substituted lower alkyl or aryl group, or OR₁₀group where R₁₀ signifies hydrogen, lower alkyl or lower alkanoyl, or Asignifies an optionally substituted alkylidene when R₇ signifies OR₁₁group where R₁₁ signifies optionally substituted lower alkanoyl or aroylgroup, and pharmaceutically acceptable salts thereof; said methodcomprising the steps of: taking a compound of formula I manufactured inaccordance with the method described above, and treating said compoundto produce a compound of formula IV.

[0021] In one embodiment of these further methods, the treatment maycomprise a dealkylation step, which may be a demethylation step. Inanother embodiment, the treatment may comprise an acylation step.Preferably, the treatment comprises both a dealkylation step and anacylation step.

[0022] In a preferred embodiment of this method, m=1, n=1, wherein R′ isCOR¹, wherein R¹ represents phenyl, and R″ is methoxy. Preferably thecompound of formula I is treated with a demethylation step and anacylation step.

[0023] In another preferred embodiment, R₄ and R₅ are both butyryl; R₆is hydrogen; R₇ is phenyl; and A is oxygen.

[0024] The demethylation step preferably comprises reacting the compoundof formula I with a methyl-acceptor in the presence of a catalyst, andcrystallizing the demethylated product. The compound of formula I may bedispersed in an organic solvent, such as ethyl acetate,1,2-dichloroethane, dichloromethane or 1,1,2,2-tetrachloroethane. Themethyl-acceptor may be pyridine and the catalyst may be aluminiumchloride. Alternatively, the methyl-acceptor and catalyst may be thesame compound, such as pyridinium chloride. The reaction may occur inthe presence of an inert gas, such as argon. Subsequently, acid, such asHCl, may be added to the reaction mixture. The addition of acid mayquench the reaction. The precipitated solid may be removed byfiltration, and is preferably washed and recrystallised.

[0025] The acylation step preferably comprises reacting the demethylatedcompound with one or more acyl-donors, such as butyric anhydride orethylchloroformate, optionally in the presence of pyridine, and acatalyst, such as 4-dimethyl-aminopyridine. The reaction may be allowedto proceed, preferably for around two hours, before the product iswashed and dried. The washing step is preferably carried out with acidand brine. The residue may be filtered and evaporated in vacuo, and thenrecrystallised, preferably from an organic solvent/petroleum ethermixture to leave the crystallized product.

[0026] A number of the moieties in formulas I, II and IV are said to be“optionally substituted”, and the methods of the invention areapplicable to a wide range of possible substitutions. Particularoptional substituents for the moieties include lower alkyl, alkoxy,halogen, nitro, amino or cyano. Thus, in this specification the term“optionally substituted” should be read, in a preferred embodiment as“optionally substituted with lower alkyl, alkoxy, halogen, nitro, aminoor cyano.”

[0027] The invention disclosed herein is exemplified by the followingexamples of preparation, which should not be construed to limit thescope of the disclosure. It is to be understood that the invention isnot to be limited to the exact details of operation or structures shown,as obvious modifications and equivalents will be apparent to thoseskilled in the art. Examples 1-7 are examples of the nitrationprocedure. Example 8 is an example of a demethylation procedure. Example9 is an example of an acylation procedure. Alternative dealkylation andacylation procedures, reactants and quantities are readily available tothose skilled in the art (see for example the Applicant's publicationsGB2344819A, EP-A-1167341 & EP-A-1167341).

EXAMPLE 1 2-Nitrophenol

[0028] To a stirred solution of phenol (0.94 g, 10 mmol) indichloromethane (10 mL) at room temperature was addedtetrabutylammoniumhydrogen sulphate (0.17 g, 5 mol %) followed byisopropyl nitrate (2.63 g, 25 mmol). Sulphuric acid (96%, 0.94 mL) wasthen added dropwise and the mixture became darker in appearance as thereaction temperature increased gently. After five minutes, the reactionmixture was poured onto water (30 mL) and the phases were separated. Theorganic phase was washed with brine and dried over anhydrous sodiumsulphate. Filtration and evaporation (40° C., water aspirator pressure)afforded a dark oil which was chromatographed over silica gel using apetroleum ether/ethyl acetate (4:1-3:1-2:1) solvent mixture for gradientelution. The faster-running component was isolated in pure form from thecolumn as yellow-orange crystals (0.9 g, 65%) of m.p. 45-46° C. andwhich was identified by NMR spectroscopy as the ortho-nitrated titleproduct, 2-nitrophenol (lit. m.p. 44-45° C., Merck Index No. 6541). Theslower-running component thereafter recovered from the column wasrecrystallised from a dichloromethane/petroleum ether mixture to givepale red crystals (0.22 g, 16%) of m.p. 112-113° C. which was identifiedby NMR spectroscopy as the para-nitrated product, 4-nitrophenol (lit.m.p. 113-114° C., Merck Index No. 6542). (81% combined yield, Ortho:Paraselectivity, 4:1).

EXAMPLE 2 3-Hydroxy4-methoxy-2-nitrobenzaldehyde

[0029] To a stirred suspension of 3-hydroxy4-methoxybenzaldehyde(isovanillin, 0.76 g, 5 mmol) in dichloromethane (10 mL) at roomtemperature was added tetrabutylammoniumhydrogen sulphate (0.085 g, 5mol %) followed by isopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid(96%, 0.76 mL) was then added dropwise to the mixture which was allowedto stir at room temperature for thirty minutes and then poured ontowater (50 mL). The phases were separated and the organic layer waswashed with brine and dried over anhydrous sodium sulphate. Filtrationand evaporation of the solvent (40° C., water aspirator pressure)afforded a solid residue which was recrystallised from adichloromethane/petroleum ether mixture to give orange crystals (0.74 g,75%) of m.p. 139-140° C., identified by NMR as the ortho-nitrated titleproduct. After concentration of the mother liquors, there was obtained asmall quantity of dark orange crystals (0.11g, 11%), corresponding (TLC)to a standard of the para-nitrated product,3-hydroxy4-methoxy-6-nitrobenzaldehyde. (86% combined yield, Ortho:Paraselectivity, 6.8:1)

EXAMPLE 3 3-Hydroxy-4-methoxy-2-nitrobenzophenone

[0030] To a stirred solution of 3-hydroxy-4-methoxybenzophenone (10.0 g,43.8 mmol) in dichloromethane (100 mL) at room temperature was addedtetrabutylammoniumhydrogen sulphate (0.74 g, 5 mol %) followed byisopropyl nitrate (11.5 9, 87.6 mmol). Sulphuric acid (96%, 10 mL) wasthen added dropwise causing a gently exothermic reaction, and, afterstirring for forty minutes, the reaction mixture was poured onto water(300 mL). The phases were separated and the aqueous phase was extractedby dichloromethane (30 mL). The combined organic phases were washed withbrine and dried over anhydrous sodium sulphate. Filtration andevaporation of the solvent (40° C., water aspirator pressure) afforded asolid residue which was recrystallised from a small volume of ethanol(96%, 10 mL) to afford yellow crystals, (7.97 g, 67%) of m.p. 137-139°C., identified by NMR as the ortho-nitrated title product. Concentrationof the mother liquors and subsequent chromatography on silica gel usinga petroleum ether:ethyl acetate solvent mixture (2:1) allowed theisolation of a small amount of a minor product, corresponding (TLC) to astandard of the para-nitrated product,3-hydroxy4-methoxy-6-nitrobenzophenone (1.43 g, 12%), m.p. 154-156° C.(79% combined yield, Ortho:Para selectivity, 5.6:1)

EXAMPLE 4 1-(3-Hydroxy-4-methoxy-2-nitrophenyl)-2-phenyl-ethanone

[0031] To a stirred solution of1-(3-hydroxy4-methoxyphenyl-2-phenyl-ethanone (8.57 g, 35.4 mmol) indichloromethane (90 mL) at room temperature was added tetrabutylammoniumsulphate (0.6 g, 5 mol %) followed by isopropyl nitrate (7.44 g, 70.8mmol). Sulphuric acid (96%, 8.5 mL) was then added dropwise causing agently exothermic reaction, and after stirring for forty minutes, thereaction mixture was poured onto water (250 mL). The phases wereseparated and the aqueous phase was extracted by dichloromethane (30mL). The combined organic phases were washed with brine and dried overanhydrous sodium sulphate. Filtration and evaporation of the solvent(40° C., water aspirator pressure) afforded a solid residue which wastriturated with a small volume of diethylether (20 mL) to afford orangecrystals, (6.9 g, 68%) of m.p. 176-177° C., identified by NMR as theortho-nitrated title product. Concentration of the mother liquors andsubsequent trituration with diethyl ether (15 mL) allowed the isolationof a small amount of a minor product, which was recrystallised from adichloromethane/heptane mixture to give yellowish crystals of m.p.142-143° C., corresponding (TLC) to a standard of the para-nitratedproduct, 1-(3-hydroxy-4-methoxy-6-nitrophenyl)-2-phenyl-ethanone (1.22g, 12%). (80% combined yield, Ortho:Para selectivity, 5.7:1)

EXAMPLE 5 2-Hydroxy-3-nitrobenzoic acid (3-Nitrosalicylic acid)

[0032] To a stirred suspension of salicylic acid (0.69 g, 5 mmol) indichloromethane (10 mL) at room temperature was addedtetrabutylammoniumhydrogen sulphate (0.085 g, 5 mol %) followed byisopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid (96%, 0.69 mL) wasthen added dropwise to the mixture which was allowed to stir at roomtemperature for thirty minutes (became a yellow solution, followed byformation of a yellow precipitate) and then poured onto water (50 mL).The yellow precipitate was filtered off and then triturated with water(10 mL). The insoluble material was filtered off and dried to affordyellow crystals, (0.42 g, 46%) of m.p. 121-122° C. identified by NMR asthe title compound (lit. m.p. 123° C., Merck Index No. 6553). The motherliqours were concentrated on a rotary evaporator (60° C., wateraspirator pressure) and recrystallised from a dichloromethane/petroleumether mixture to give yellow/orange crystals (0.35 g, 39%) of m.p.226-228° C., identified by NMR as 2-hydroxy-5-nitrobenzoic acid(5-nitrosalicylic acid) (lit. m.p. 228-230° C., Merck Index No. 6554).(85% combined yield, Ortho:Para selectivity, 1.2:1)

EXAMPLE 6 3-Hydroxy-2-nitrobenzaldehyde and 3-hydroxy4-nitrobenzaldehyde

[0033] To a stirred suspension of 3-hydroxybenzaldehyde (0.61 g, 5 mmol)in dichloromethane (10 mL) at room temperature was addedtetrabutylammoniumhydrogen sulphate (0.085 g, 5 mol%) followed byisopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid (96%, 0.61 mL) wasthen added dropwise to the mixture causing a gentle rise in temperature.The reaction mixture was then stirred for fifteen minutes (became a darkbrown suspension) and then poured onto water (50 mL). The phases wereseparated and the aqueous phase was extracted by dichloromethane (10mL). The combined organic layers were washed by brine, dried overanhydrous sodium sulphate and filtered. Evaporation of the solvent (40°C., water aspirator pressure) afforded a brown solid which was thenchromatographed over silica gel using a petroleum ether/ethyl acetatesolvent mixture (2:1). The faster-running component was obtained fromthe column as a yellow solid (0.19 g, 23%), identified by NMR as3-hydroxy-4-nitrobenzaldehyde. The slower-running component was alsoisolated as a yellow solid, identified by NMR as3-hydroxy-2-nitrobenzaldehyde (0.56 g, 67%). (90% combined yield, bothproducts are ortho-nitrated, no para-nitro isomer was detected).

EXAMPLE 7 2,4-Difluoro-6-nitrophenol

[0034] To a stirred solution of 2,4-difluorophenol (0.65 g, 5 mmol) indichloromethane (7 mL) at room temperature was addedtetrabutylammoniumhydrogen sulphate (0.085 g, 5 mol %) followed byisopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid (96%, 0.65 mL) wasthen added dropwise to the mixture causing gentle reflux of the solvent.The reaction mixture was then stirred for fifteen minutes and thenpoured onto water (50 mL). The phases were separated and the aqueousphase was extracted by dichloromethane (10 mL). The combined organiclayers were washed by brine, dried over anhydrous sodium sulphate andfiltered through a short pad of silica gel. Evaporation of the solvent(40° C., water aspirator pressure) afforded a yellow solid, identifiedby NMR as the title compound (0.73 g, 83%). (ortho-selectivity 100%, nonitro-isomers detected).

EXAMPLE 8 3,4-dihydroxy-2-nitrobenzophenone

[0035] To a stirred suspension of 3-Hydroxy4-methoxy-2-nitrobenzophenone(8.3 g, 30.38 mmol) in 1,2-dichloroethane (100 ml) at room temperatureunder argon was added aluminium chloride (4.46 g, 33.45 mmol) in oneportion followed by pyridine (9.61 g, 9.81 ml, 121.5 mmol) giving riseto an exothermic reaction. the mixture was stirred at reflux for onehour, allowed to cool to room temperature and then poured onto ice-water(300 ml). Hydrochloric acid (2N, 70 ml) was added and the mixture wasstirred for one hour (initial orange precipitate gradually became yellowin appearance. The solid was removed by filtration, washed by water (30ml) and dried under vacuum to give the product as a yellow solid 6.99g,(89%) of melting point 153-155° C. The organic phase of the filtrate wasseparated and the aqueous phase was extracted by dichloromethane (20ml). The combined organic phases were washed by brine (30 ml), driedover anhydrous sodium sulphate and the solvent removed on a rotaryevaporator (bath temp. 40° C.) to leave a yellow solid (0.7 g) which wasnot purified further.

EXAMPLE 9 butyric acid, 3-benzoyl-6-butyrloxy-2-nitro-phenyl ester[3,4-dibutyryloxy-2-nitrobenzophenone]

[0036] To a stirred solution of(3,4-dihydroxy-2-nitro-phenyl)-phenyl-methanone (0.34 g, 1.29 mmol) (5mL) [3,4-dihydroxy-2-nitrobenzophenone in dichloromethane] at roomtemperature was added pyridine (0.41 g, 5.19 mmol), butyric anhydride(0.82 g, 5.19 mmol) and 4-dimethyl-aminopyridine (0.01 g). The resultingsolution was stirred for one hour and then extracted by cold water, 1NHCl and brine, then dried over sodium sulphate. After filtration andevaporation in vacuo the residue was chromatographed over silica gelusing an ethyl acetate/petroleum ether mixture to give off-whitecrystals of m.p 55 to 57° C.

[0037] It will be appreciated that the invention described above may bemodified.

1. A method for the preparation of compounds of formula I

wherein: the terms R′ and R″ may be the same or different and represent:hydrogen; lower alkyl; hydroxy; lower alkoxy; halogen; the group —CO—R¹,wherein R¹ signifies hydrogen, hydroxy, alkylaryl, alkylheterocycloalkylor optionally substituted saturated or partially unsaturated lower alkylor aryl group, or R¹ signifies the group —O—R², wherein R² signifies alower alkyl or aryl group; the group —C═N—R^(a), wherein R^(a) signifiesNHR^(a), wherein R^(a) represents optionally substituted lower alkyl oraryl group, or OR^(b) group, where R^(b) signifies hydrogen, lower alkylor lower alkanoyl; the group —C—R^(c)R^(d), where R^(c) signifies anoptionally substituted alkylidene, where R^(d) represents OR^(e) groupwhere R^(e) signifies optionally substituted lower alkanoyl or arylgroup; or R′ and R″ taken together signify an optionally substututedsaturated or partially unsaturated carbocyclic ring; m and n areindependently 0, 1 or 2; the term lower alkyl means a carbon chain,straight or branched, containing from one to six carbon atoms; the termhalogen means fluorine, chlorine, bromine or iodine; the termheterocycloalkyl means a five or six-membered cyclic ring incorporatingone or two atoms of oxygen, sulphur or nitrogen; the term aryl means aphenyl or naphthyl group optionally substituted by alkoxy, halo or nitrogroups; said method comprising reacting a phenolic compound of formulaII:

wherein the terms R′ and R″, m and n are defined above, with an alkylnitrate of formula (III) R³—ONO₂  FORMULA III where R³ represents analkyl group straight or branched, containing from one to sixteen carbonatoms, or R³ represents a cycloalkyl group containing either five or sixcarbon atoms.
 2. A method according to claim 1 wherein the reaction isconducted in the presence of a phase transfer catalyst.
 3. A methodaccording to claim 1, wherein the acid catalyst is a mineral acid or anorganic acid.
 4. A method according to claim 1, wherein the acidcatalyst is sulphuric acid.
 5. A method according to claim 1, whereinthe acid catalyst is a Lewis acid catalyst.
 6. A method according toclaim 1 wherein the alkyl nitrate is isopropyl nitrate.
 7. A methodaccording to claim 1 wherein the alkyl nitrate is isobutyl nitrate.
 8. Amethod according to claim 1 wherein the alkyl nitrate is isoamyl nitrate(isopentyl nitrate).
 9. A method according to claim 1 wherein the alkylnitrate is isooctyl nitrate (2-ethylhexyl nitrate).
 10. A methodaccording to claim 1 wherein the phenolic compound is3-hydroxy4-methoxybenzophenone.
 11. A method according to claim 1,wherein R′ and R″ may be the same or different and signify saturated orpartially unsaturated lower alkyl or aryl group, optionally substitutedwith lower alkyl, alkoxy, halogen, nitro, amino or cyano.
 12. A methodfor the preparation of a compound of formula IV:

where R₄ and R₅ are the same or different and signify hydrogen,optionally substituted lower alkanoyl or aroyl, optionally substitutedlower alkoxycarbonyl, or optionally substituted lower alkylcarbamoyl; R₆signifies hydrogen or optionally substituted alkanoyl or aroyl group; R₇signifies optionally substituted saturated or partially unsaturatedlower alkyl or aryl group, or taken together with R₆ signifies anoptionally substituted saturated or partially unsaturated carbocyclicring; A signifies oxygen or NR₈ group, where R₈ signifies NHR₉ where R₉signifies optionally substituted lower alkyl or aryl group, or OR₁₀group where R₁₀ signifies hydrogen, lower alkyl or lower alkanoyl, or Asignifies an optionally substituted alkylidene when R₇ signifies OR₁₁,group where R₁₁ signifies optionally substituted lower alkanoyl or aroylgroup, and pharmaceutically acceptable salts thereof; said methodcomprising the steps of: taking a compound of formula I manufactured inaccordance with the method of claim 1, and treating said compound toproduce a compound of formula IV.
 13. A method according to claim 12,wherein the phenolic compound of formula II is3-hydroxy4-methoxybenzophenone, and the intermediate compound of formulaI is 3-hydroxy4-methoxy-2-nitrobenzophenone.
 14. A method according toclaim 12, wherein the compound of formula IV is butyric acid,3-benzoyl-6-butyryloxy-2-nitrophenyl ester.
 15. A method according toclaim 12, wherein the treatment comprises a dealkylation step.
 16. Amethod according to claim 12, wherein the dealkylation step comprises ademethylation step.
 17. A method according to claim 16, wherein thedemethylation step comprises reacting the compound of formula I with amethyl acceptor, in the presence of a catalyst, and recrystallizing thedemethylated product.
 18. A method according to claim 12, wherein thetreatment comprises an acylation step.
 19. A method according to claim18, wherein the acylation step comprises reacting the compound offormula I, or its demethylated equivalent with an acyl-donor in thepresence of a catalyst.
 20. A method according to claim 12, wherein m=1,n=1, R′ is —COR¹, wherein R¹ represents phenyl, and R″ is a methoxygroup; the treatment comprising a demethylation step and an acylationstep.
 21. A method according to claim 20, wherein R₄ and R₅ are bothbutyryl; R₆ is hydrogen; R₇ is phenyl; and A is oxygen.
 22. A medicamentfor use as a COMT inhibitor comprising a composition formed by themethod according to claim
 12. 23. A medicament for use in treatingcentral and peripheral nervous system disorders comprising a compositionformed by the method according to claim 12.